PROJECT SUMMARY The objective of our program is to develop a safe and effective nonopioid analgesic for the treatment of neuropathic pain, such as pain associated with chemotherapy-induced peripheral neuropathy, that targets an isoform of the voltage-gated sodium ion channel, NaV1.7. Voltage-gated sodium channels are involved in the transmission of nociceptive signals from their site of origin in the peripheral terminals of DRG neurons to the synaptic terminals in the dorsal horn. Ten mammalian isoforms exist, NaV1.1?1.9 and NaX. NaV1.7 is the most abundant tetrodotoxin-sensitive sodium channel in small diameter myelinated and unmyelinated afferents, where it has been shown to modulate excitability and set the threshold for action potentials. Humans lacking functional NaV1.7 due to a rare genetic condition are unable to experience almost all types of pain. Efforts to develop systemic inhibitors of NaV1.7 have been complicated by the challenge of achieving selectivity over other NaV isoforms expressed in the diaphragm, phrenic nerve, heart and central nervous system that are critical for safety. SiteOne Therapeutics has discovered a series of potent, state-independent NaV1.7 inhibitors that exhibit >1000-fold selectivity over other human isoforms. Work conducted under this program will support advancement of a lead candidate into clinical development as a therapeutic for neuropathic pain.